Synthesis Of Benzodiazepine Derivatives

ABSTRACT

The invention relates to processes for the synthesis of benzodiazepine derivatives of Formula I:

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/750,339 filed on Feb. 5, 2018, which application is a 35 U.S.C. § 371filing of International Application No. PCT/GB2016/052442, filed on Aug.5, 2016, which claims priority to PCT/GB2015/052291, filed Aug. 7, 2015,and Great Britain patent application number 1513979.3 filed Aug. 7,2015. The entire contents of these applications are incorporated byreference herein, in their entirety.

FIELD OF THE INVENTION

The invention relates to the synthesis of benzodiazepine derivatives.

BACKGROUND

Benzodiazepine derivatives such as YF476 act as an antagonists atgastrin/CCK₂ receptors (Semple et al. J Med Chem 1997; 40: 331-341).

Further benzodiazepine derivatives are described in WO93/16999, Yano etal. Chem Pharm Bull (Tokyo) 1996; 44: 2309-2313, Murphy et al. ClinPharmacol Ther 1993; 54: 533-39 and Kramer et al. Biol Psychiatry 1995;37: 462-466.

The synthesis of the type of benzodiazepine derivatives described inSemple et al. involves coupling of an isocyanate, for example

3-[N-(tert-butyloxycarbony)methylamino]phenyl isocyanate, with an amine,for example(R)-3-amino-1[(tert-butylcarbonyl)-methyl]-2,3-dihydro-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one.The isocyanate is prepared using potentially explosive azide chemistry.

There remains a need for improved synthetic processes for the productionof this type of benzodiazepine derivatives which avoid the need forpotentially explosive azide chemistry. In addition, there remains a needfor efficacious gastrin/cholecystokinin 2 (CCK₂) receptor antagonistswhich can successfully be used in pharmaceutical compositions to providebeneficial properties in terms of pharmacokinetics, improvedbioavailability, avoidance of a requirement for administration withfood, minimisation of processing steps required in formulation, and thelike.

SUMMARY OF THE INVENTION

In a first aspect, the present invention provides a process forproducing a compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein

R₁ is:

-   -   (i) —CH₂C(O)C(R₂)(R₃)—L—R₄ or —CH₂CHOHC(R₂)(R₃)—L—R₄, in which:        -   R₂ and R₃ are each, independently, H or C₁₋₃ aliphatic,            halo, or C₁₋₃ haloaliphatic, or wherein R₂ and R₃ together            with the intervening carbon atom to which they are bonded,            form a C₃₋₆ carbocyclic moiety;        -   L is a bond or C₁₋₃ alkylene; and        -   R₄ is —OR₅ or —SR₅, wherein R₅ is hydrogen, optionally            substituted alkyl (e.g. C₁₋₆ alkyl, such as methyl), a            protecting group or —C(O)R₆, wherein R₆ is optionally            substituted aliphatic, heteroaliphatic, aromatic or            heteroaromatic moiety;    -   (ii) —CH₂CHOH(CH₂)_(a)R₇ or —CH₂C(O)(CH₂)_(a)R₈ in which a is 0        or 1 and R₇ and R₈ are selected from alkyl and cycloalkyl groups        and saturated heterocyclic groups optionally substituted at a        hetero-atom; or    -   (iii) an optionally substituted aliphatic moiety;        W and X are, independently, hydrogen, halo, C₁₋₈ alkyl or C₁₋₈        alkoxy; and rings A and B are each, independently, a monocyclic        aryl or heteroaryl, optionally substituted with one or more        substituents independently selected from halo, hydroxy, amino,        nitro, carboxyl, carboxamido, cyano, —SO₃H, and optionally        substituted C₁₋₈ alkyl, C₁₋₈ alkoxy, C₁₋₈ alkylamino or di(C₁₋₈        alkyl)amino,        wherein any one or more substituent on R₁, ring A or ring B may        be unprotected or in a protected form;        wherein the process comprises:    -   (a) providing a reaction mixture by adding a compound of formula        (I-A), a compound of formula (I-B) and a phosgene synthetic        equivalent or phosgene to an aprotic solvent, to form a compound        of formula (I)

or

-   -   (b) providing a reaction mixture by adding a compound of formula        (I-C), and a phosgene synthetic equivalent or phosgene, to an        aprotic solvent and, subsequently, adding a compound of formula        (I-B) to the reaction mixture to form a compound of formula (I):

wherein the phosgene synthetic equivalent is carbonyldiimidazole (CDI),diphosgene, triphosgene, a chloroformate (e.g. 4-nitrophenylchloroformate) or disuccinimidyl carbonate.

The phosgene synthetic equivalent or phosgene may, for example, be CDI.

In some embodiments, the process comprises the additional step ofdeprotection to remove one or more protecting groups wherein any one ormore substituents on R₁, ring A or ring B is in a protected form. Forexample, as indicated above protecting groups may be present on any oneor more substituent on R₁, ring A or ring B in the compound of formula(I-A), (I-B) or (I-C) and, in these embodiments, the process maycomprise the additional step of deprotection to remove the one or moreprotecting groups to form a compound of formula (I), or any embodimentthereof as described herein. Thus, the process may comprise providing areaction mixture by adding a compound of formula (I-A), a compound offormula (I-B) and a phosgene synthetic equivalent or phosgene to anaprotic solvent, to form a compound of formula (I) via initial formationof a protected compound (I) and the additional step of deprotection toremove one or more protecting groups to form a compound of formula (I);or providing a reaction mixture by adding a compound of formula (I-C),and a phosgene synthetic equivalent or phosgene, to an aprotic solventand, subsequently, adding a compound of formula (I-B) to the reactionmixture to form a compound of formula (I) via initial formation of aprotected compound (I) and the additional step of deprotection to removeone or more protecting groups to form a compound of formula (I)

In some embodiments, wherein the process comprises step (a) of providinga reaction mixture by adding a compound of formula (I-A), a compound offormula (I-B) and a phosgene synthetic equivalent or phosgene to anaprotic solvent, to form a compound of formula (I), the reaction mixtureis maintained at a temperature of no more than 50° C., no more than 40°C. or preferably no more than 30° C.

Wherein the process comprises step (a) of providing a reaction mixtureby adding a compound of formula (I-A), a compound of formula (I-B) and aphosgene synthetic equivalent or phosgene to an aprotic solvent, to forma compound of formula (I), the compound of formula (I-A), the compoundof formula (I-B) and the phosgene synthetic equivalent or phosgene maybe added to the solvent in any order. Addition of these compounds toprovide a reaction mixture results in reaction in the reaction mixtureto form a compound of formula (I). Preferably the compound of formula(I-A) and the phosgene synthetic equivalent or phosgene are added to thesolvent prior to addition of the compound of formula (I-B). In someembodiments, the temperature of the reaction mixture is maintained at atemperature of 0-10° C., preferably 0-5° C., during addition of thecompound of formula (I-A) and the phosgene synthetic equivalent orphosgene to the solvent. During subsequent addition of the compound offormula (I-B), the reaction mixture is preferably maintained at atemperature no more than 30° C., for example at 15-20° C.

In step (a) the aprotic solvent may, for example, be dichloromethane,acetonitrile or toluene, preferably dichloromethane.

Wherein the process comprises step (b) of providing a reaction mixtureby adding a compound of formula (I-C) and a phosgene syntheticequivalent or phosgene, to an aprotic solvent and, subsequently, addinga compound of formula (I-B) to the reaction mixture, addition of thesecompounds results in reaction in the reaction mixture to form a compoundof formula (I). The process of step (b) may comprise heating thereaction mixture to a temperature of at least 40° C., preferably atleast 50° C., before addition of the compound of formula (I-B). Theprocess of step (b) may, as an alternative to heating, comprise adding anon-aqueous base to the reaction before addition of the compound offormula (I-B).

In step (b) the aprotic solvent may, for example, be dichloromethane,acetonitrile or toluene, preferably acetonitrile.

It will be appreciated that definitions for rings A and B, R₁, W and Xin compounds of formula (I-A), (I-B) and (I-C), or any embodimentsthereof as described herein, correspond to those substituents, orprotected forms thereof, as present in formula (I), or any embodimentsthereof as described herein. Thus, in formulae (I-A) and (I-C), ring Ais a monocyclic aryl or heteroaryl, optionally substituted with one ormore substituents independently selected from halo, hydroxy, amino,nitro, carboxyl, carboxamido, cyano, —SO₃H, and optionally substitutedC₁₋₈ alkyl, C₁₋₈ alkoxy, C₁₋₈ alkylamino or di(C₁₋₈ alkyl)amino, whereinany one or more substituent on ring A may be unprotected or in aprotected form; and in formula (I-B) W and X are, independently,hydrogen, halo, C₁₋₈ alkyl or C₁₋₈ alkoxy; ring B is a monocyclic arylor heteroaryl, optionally substituted with one or more substituentsindependently selected from halo, hydroxy, amino, nitro, carboxyl,carboxamido, cyano, —SO₃H, and optionally substituted C₁₋₈ alkyl, C₁₋₈alkoxy, C₁₋₈ alkylamino or di(C₁₋₈ alkyl)amino, wherein any one or moresubstituent on ring B may be unprotected or in a protected form; and R₁is: (i) —CH₂C(O)C(R₂)(R₃)—L—R₄ or —CH₂CHOHC(R₂)(R₃)—L—R₄, in which: R₂and R₃ are each, independently, H or C₁₋₃ aliphatic, halo, or C₁₋₃haloaliphatic, or wherein R₂ and R₃ together with the intervening carbonatom to which they are bonded, form a C₃₋₆ carbocyclic moiety; L is abond or C₁₋₃ alkylene; and R₄ is —OR₆ or —SR₅, wherein R₅ is hydrogen,optionally substituted alkyl (e.g. C₁₋₆ alkyl, such as methyl), aprotecting group or —C(O)R₆, wherein R₆ is optionally substitutedaliphatic, heteroaliphatic, aromatic or heteroaromatic moiety; (ii)—CH₂CHOH(CH₂)_(a)R₇ or —CH₂C(O)(CH₂)_(a)R₈ in which a is 0 or 1 and R₇and R₈ are selected from alkyl and cycloalkyl groups and saturatedheterocyclic groups optionally substituted at a hetero-atom; or (iii) anoptionally substituted aliphatic moiety, wherein any one or moresubstituent on R₁ may be unprotected or in a protected form.

Any of the above embodiments of a process of the invention may, forexample, be for producing a compound wherein at least one of ring A andring B is unsubstituted or substituted phenyl or pyridyl. At least oneof ring A and ring B may be unsubstituted, monosubstituted ordisubstituted phenyl or unsubstituted, monosubstituted or disubstituted2-, 3- or 4-pyridyl. Where ring A and/or ring B is substituted withoptionally substituted C₁₋₈ alkyl, C₁₋₈ alkoxy, C₁₋₈ alkylamino ordi(C₁₋₈ alkyl)amino, the optional substituents on C₁₋₈ alkyl, C₁₋₈alkoxy, C₁₋₈ alkylamino and di(C₁₋₈ alkyl)amino include any substituentas described herein for substituents on an aliphatic group, for example,halo, —NO₂, —CN, amino, C₁₋₈ alkylamino, di(C₁₋₈ alkyl)amino, —S(O)H or—CO₂H. In some embodiments, ring A is phenyl having a meta substituentchosen from NHMe, NMeEt, NEt₂, F, Cl, Br, OH, OCH₃, NH₂, NMe₂, NO₂, Me,(CH₂)_(n)—CO₂H, CN, CH₂NMe₂, NHCHO and (CH₂)_(n)—SO₃H where n is 0-2;unsubstituted phenyl or 2-, 3- or 4-pyridyl optionally with asubstituent selected from F, Cl, CH₃ and CO₂H; and ring B is 2-, 3- or4-pyridyl or phenyl. As described above, any one or more substituent onring A or ring B may be unprotected or in a protected form.

In any of the above embodiments, W and X may independently be H, halo,C₁₋₃ alkyl or C₁₋₃ alkoxy. Preferably, W and X are both H.

Any of the above embodiments may, for example, be for producing acompound wherein R₁ is —CH₂C(O)C(R₂)(R₃)—L—R₄ or —CH₂CHOHC(R₂)(R₃)—L—R₄,preferably wherein R₁ is —CH₂C(O)C(R₂)(R₃)—L—R₄.

Alternatively, a process of the invention as described herein may be forproducing a compound wherein R₁ is —CH₂CHOH(CH₂)_(a)R₇ or—CH₂C(O)(CH₂)_(a)R₈ in which a is 0 or 1 and R₇ and R₈ are,independently, alkyl, cycloalkyl or a saturated heterocyclic groupoptionally substituted at a hetero-atom. In some embodiments, R₇ and R₈are selected from C₁₋₈ alkyl, C₃₋₈ cycloalkyl (which may beunsubstituted or substituted with one or more C₁₋₈ alkyl groups); andsaturated heterocyclic groups of formulae (i-a) and (i-b):

in which R₉ is H or C₁₋₃ alkyl or C₁₋₃ acyl and b is 1 or 2. In someembodiments, R7 is C4-7 linear or branched alkyl and R₈ is C₁₋₇(preferably C₄₋₇) linear or branched alkyl.

In any of the above embodiments of the invention, a compound of formula(I-A) may be a compound of formula (II-A) as described below. In any ofthe above embodiments of the invention, a compound of formula (I-B) maybe a compound of formula (II-B) as described below. In any of the aboveembodiments of the invention, a compound of formula (I-C) may be acompound of formula (II-C) as described below.

The compound of formula (I) may be a compound of formula (II):

or a pharmaceutically acceptable salt thereof, wherein R₂, R₃, L and R₄are as defined above in relation to formula (I). In an embodiment of theprocess of the invention where the compound of formula (I) is a compoundof formula (II), the compound of formula (I-A) is a compound of formula(II-A), the compound of formula (I-B) is a compound of formula (II-B)and the compound of formula (I-C) is a compound of formula (II-C).

wherein PG is a protecting group, preferably a Boc protecting group. Itwill be appreciated that, in this embodiment or any of the furtherembodiments thereof as described herein, a protected form of compound(II):

is initially formed in step (a) or (b) as described above and theprocess comprises the additional step of deprotection as described aboveto remove PG and form a compound of formula (II).

In any of the above embodiments, where R₂ and R₃ together with theintervening carbon atom to which they are bonded, form a carbocyclicmoiety, the carbocyclic moiety may be a C₃₋₄ carbocyclic moiety.

In any of the above embodiments, R₂ and R₃ may each, independently, be Hor C₁₋₂ alkyl and L may be a bond or C₁₋₃ alkylene. In some embodiments,R₂ and R₃ may each, independently, be C₁₋₂ alkyl and L may beC₁₋₃alkylene. In some embodiments, R₂ and R₃ may each, independently, beH or C₁₋₂ alkyl and L may be C₁ alkylene (—CH₂—). In some embodiments,R₂ and R₃ may each, independently, be C₁₋₂ alkyl and L may be C₁alkylene (—CH₂—).

In any of the above embodiments, where R₁ is —CH₂C(O)C(R₂)(R₃)—L—R₄ or—CH₂CHOHC(R₂)(R₃)—L—R₄ (preferably —CH₂COC(R₂)(R₃)—L—R₄), R₄ may be —OR₅or —SR₅ wherein R₅ is hydrogen, methyl or —C(O)R₆, wherein R₆ isoptionally substituted aliphatic, heteroaliphatic, aromatic orheteroaromatic moiety. In some embodiments, R₆ is optionally substitutedaliphatic, for example R₆ is substituted or unsubstituted C₁₋₆aliphatic, preferably substituted or unsubstituted C₁₋₃ aliphatic, morepreferably methyl. Preferably, R₄ is —OR₅ and R₅ is —C(O)R₆.

The compounds of formula (I), (I-B), (II) and (II-B) contain a chiralcentre at the position marked * and may exist in enantiomeric forms.Compounds may be provided as a racemic mixture of enantiomers, anon-racemic mixture of enantiomers or as a single enantiomer inoptically pure form, for example the R-enantiomer at *:

A compound of formula (I) or (II) may be, for example, a compoundselected from:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound may be selected from:

or a pharmaceutically acceptable salt thereof.

A compound of formula (II) may be a compound of formula (III):

or a pharmaceutically acceptable salt thereof, wherein R₁₁ is selectedfrom

wherein R6 is as defined for any of the embodiments of formula (I) or(II) above. In some embodiments, the compound may be a compound offormula (IV):

or a pharmaceutically acceptable salt thereof. Preferably, R₁₁ isselected from:

In a preferred embodiment, the compound of formula (I) or (II) is acompound (TR):

or a pharmaceutically acceptable salt thereof. Compound (TR) contains achiral centre and therefore exists as two enantiomers, designated (TR2)(the R-enantiomer) and (TR3) (the S-enantiomer).

In a process of the invention, (TR) may be provided as the racemicmixture of the enantiomers (TR2) and (TR3), a non-racemic mixture of theenantiomers (TR2) and (TR3) or as a single enantiomer (TR2 or TR3) inoptically pure form. The racemic mixture of (TR2) and (TR3) isdesignated “(TR1)” herein.

In a preferred embodiment, the compound of formula (I) or (II) is acompound (TR-A):

or a pharmaceutically acceptable salt thereof. It will be appreciatedthat in this embodiment, the compound of (II-B) is a compound where—CH₂C(O)C(R₂)(R₃)—L—R₄ is —CH₂C(O)C(Me)(Me)CH₂—OC(O)Me. Thus, thecompound of formula (I-A) may be a compound of formula (II-A) and theadditional step of deprotection as described above may occur to removePG and form a compound (TR-A). The compound (TR-A) may be provided asthe racemic mixture (TR1-A) of the enantiomers (TR2-A) (theR-enantiomer) and (TR3-A) (the S-enantiomer), a non-racemic mixture ofthe enantiomers (TR2-A) and (TR3-A) or as a single enantiomer (TR2-A orTR3-A) in optically pure form.

In another embodiment, the compound of formula (I) or (II) may be YF476:

or a pharmaceutically acceptable salt thereof.

In an embodiment of the process of the invention, the process may be forproducing a compound of formula (TR2-A):

wherein the process comprises:providing a reaction mixture by adding a compound of formula (II-A), acompound of formula (II-Ba) and a phosgene synthetic equivalent orphosgene to an aprotic solvent, to form a compound of formula (TR2-A)via initial formation of a compound of formula (TR2-A-PG)

wherein PG is a protecting group, optionally a Boc protecting group; and

deprotecting the compound of formula (TR2-A-PG) to form a compound offormula (TR2-A).

The acetyl group of a compound of formula (TR2-A) may be removed to forma compound of formula (TR2).

A Boc protecting group may be deprotected under conditions known to aperson of skill in the art, for example, by exposure to a strong acidsuch as TFA or HCl.

In an embodiment of the process of the invention, the process may be forproducing a compound of formula (TR2):

wherein the process comprises:providing a reaction mixture by adding a compound of formula (II-A), acompound of formula (II-Bb) and a phosgene synthetic equivalent orphosgene to an aprotic solvent, to form a compound of formula (TR2) viainitial formation of a compound of formula (TR2-PG)

wherein PG is a protecting group, optionally a Boc protecting group; anddeprotecting the compound of formula (TR2-PG) to form a compound offormula (TR2).

In a second aspect, the invention provides a compound obtained by aprocess according to the first aspect of the invention.

In a third aspect, the invention provides a compound of formula (II-C):

wherein PG is a protecting group, preferably a Boc protecting group.

An alternative process for producing a compound of formula (I), or apharmaceutically acceptable salt thereof, comprises providing a reactionmixture by adding a compound of formula (V-A), a reagent or reagentscapable of rearranging the compound of formula (V-A) to form aisocyanate intermediate of formula (V-B), and a compound of formula(I-B) to a non-aqueous solvent to form a compound of formula (I)

The reaction to form intermediate (V-B) may proceed via an N-bromoderivative (V-B)

In this embodiment, the reagent or reagents capable of arranging thecompound of formula (V-A) to form an isocyanate intermediate of formula(V-B) comprise a brominating agent, for example N-bromosuccinimide, anda base, for example DBU (1,8-diazabicyclo[5.4.0]undec-7-ene). Thenon-aqueous solvent may be an aprotic solvent, for example toluene.Intermediates (V-B) and (V-Bi) are formed and reacted with a compound offormula (I-B) in situ.

In the above process, the compounds of formula (I-B) and formula (I) andring A of the compounds of formula (V-A), (V-B) and (V-Bi) are asdefined above in any embodiment of the first aspect of the invention.

2-(2-Aminobenzoyl)pyridine may be utilised in the preparation of acompound of formula (II-B), or embodiments thereof, as described herein.2-(2-aminobenzoyl)pyridine may be prepared by a process comprisingreacting morpholine with isatoic anhydride to formN-(2-aminobenzoyl)morpholine and reacting N-(2-aminobenzoyl)morpholinewith 2-lithiumpyridine to form 2-(2-aminobenzoyl)pyridine.2-lithiumpyridine may be prepared by reacting 2-bromopyridine withn-butyl lithium. This process may be carried out in an aprotic solventsuch as toluene.

DETAILED DESCRIPTION OF THE INVENTION

The meanings of terms used in the specification of the presentapplication will be explained below, and the present invention will bedescribed in detail.

The term “aliphatic”, as used herein, means a substituted orunsubstituted straight-chain, branched or cyclic hydrocarbon, which iscompletely saturated or which contains one or more units ofunsaturation, but which is not aromatic. Aliphatic groups includesubstituted or unsubstituted linear, branched or cyclic alkyl, alkenyl,alkynyl groups and hybrids thereof, such as (cycloalkyl)alkyl,(cycloalkenyl)alkyl or (cycloalkyl)alkenyl. In various embodiments, analiphatic group has 1 to 12, 1 to 8, 1 to 6, or 1 to 3 carbons. Forexample, C₁₋₃ aliphatic encompasses straight chain and branched C₁₋₃alkyl, alkenyl and alkynyl and cyclopropyl. The term “heteroaliphatic”means an aliphatic group in which one or more carbon atom is replaced bya heteroatom. The term “heteroatom” refers to nitrogen (N), oxygen (O),or sulfur (S).

The term “alkylene” refers to a bivalent alkyl group. An “alkylene” is amethylene or polymethylene group, i.e., —(CH₂)_(n)—, wherein n is apositive integer. An alkylene may be unsubstituted or substituted. Asubstituted alkylene is an alkylene group in which one or more methylenehydrogen atoms is replaced with a substituent. Suitable substituentsinclude those described below for a substituted aliphatic group. Analkylene chain also may be substituted at one or more positions with analiphatic group or a substituted aliphatic group.

The term “carbocyclic moeity” refers to a cyclic aliphatic group andincludes, for example, cycloalkyl moieties.

The term “aryl” refers to a C₆₋₁₄ (preferably C₆₋₁₀) aromatichydrocarbon, comprising one to three rings, each of which is optionallysubstituted. Aryl groups include, without limitation, phenyl, naphthyl,and anthracenyl. In some embodiments, two adjacent substituents on anaryl ring, taken together with the intervening ring atoms, form anoptionally substituted fused 5- to 6-membered aromatic or 4- to8-membered non-aromatic ring having 0-3 ring heteroatoms selected fromthe group consisting of N, O and S. Thus, the term “aryl”, as usedherein, includes groups in which an aromatic ring is fused to one ormore heteroaromatic, cycloaliphatic, or heterocyclic rings, where theradical or point of attachment is on the aromatic ring.

The terms “heteroaryl” and “heteroar-” refer to an aromatic group having5 to 14 ring atoms, preferably 5,6,9, or 10 ring atoms and having, inaddition to carbon atoms, from one to four heteroatoms as ring atoms.The term “heteroatom” refers to N, O, or S. In some embodiments, twoadjacent substituents on the heteroaryl, taken together with theintervening ring atoms, form an optionally substituted fused 5- to6-membered aromatic or 4- to 8-membered non-aromatic ring having 0-3ring heteroatoms selected from the group consisting of N, O and S. Thus,the terms “heteroaryl” and “heteroar-”, as used herein, also includegroups in which a heteroaromatic ring is fused to one or more aromatic,cycloaliphatic, or heterocyclic rings, where the radical or point ofattachment is on the heteroaromatic ring.

As used herein, “halo” refers to fluoro, chloro, bromo or iodo.

As used herein, “haloaliphatic” refers to an aliphatic moiety as definedabove, substituted by one or more halo moieties.

As used herein, “alkoxy” refers to a —O-alkyl moiety. The alkyl is asdefined herein and, accordingly, may optionally be substituted asdefined herein for optional substituents of an aliphatic moiety.

As used herein, “carboxamido” refers to a —C(O)NR₂ moiety, wherein eachR is, independently, H or aliphatic, preferably H.

As used herein, the term “comprises” means “includes, but is not limitedto.”

The term “substituted”, as used herein, means that a hydrogen radical ofa designated moiety is replaced with the radical of a specifiedsubstituent, provided that the substitution results in a stable orchemically feasible compound. The phrase “one or more substituents”, asused herein, refers to a number of substituents that equals from one tothe maximum number of substituents possible based on the number ofavailable bonding sites. Unless otherwise indicated, where multiplesubstituents are present, substituents may be either the same ordifferent.

An aryl or heteroaryl group may be optionally substituted. Suitablesubstituents on the unsaturated carbon atom of an aryl or heteroarylgroup include halo, —NO₂, —CN, —R′, —C(R′)═C(R)₂, —OR′, —SR′, —S(O)R′,—SO₂R′, —SO₃R′, —SO₂N(R)₂, —N(R′)₂, —NR′C(O)R′, —NR′C(O)N(R′)₂,—NR′CO₂R′, —NR′SO₂R′, —NRSO₂N(R)₂, —O—C(O)R′, —O—CO₂R′, —OC(O)N(R),—C(O)R′, —CO₂R′, —C(O)N(R)₂, —P(O)(R)₂, —P(O)(OR′)₂, —O—P(O)—OR′,wherein R′, independently, is hydrogen or an optionally substitutedaliphatic, heteroaliphatic, aromatic or heteroaromatic moiety, or twooccurrences of R′ are taken together with their intervening atom(s) toform an optionally substituted 5-7-membered aromatic, heteroaromatic,cycloaliphatic, or heterocyclic ring.

An aliphatic or heteroaliphatic group, including carbocyclic orheterocyclic rings, may be “optionally substituted”. Unless otherwisedefined, suitable substituents on the saturated carbon of an optionallysubstituted aliphatic or heteroaliphatic group, are selected from thoselisted above for the unsaturated carbon of an aryl or heteroaryl groupand additionally include the following: ═O, ═S, ═C(R″)₂, where R″ ishydrogen or an optionally substituted C₁₋₆ aliphatic group.

In addition to the substituents defined above, optional substituents onthe nitrogen of a non-aromatic heterocyclic ring also include and aregenerally selected from R′, —N(R)₂, —C(O)R′, —C(O)OR′, —S(O)₂R′,—S(O)₂N(R)₂, wherein each R′ is defined above. A ring nitrogen atom of aheteroaryl or non-aromatic heterocyclic ring also may be oxidized toform the corresponding N-hydroxy or N-oxide compound.

As used herein, a “protected form” of a compound refers to a compound inwhich a functional moiety is protected by a protecting group. Thefunctional moiety to be protected may be a hydroxyl, carboxyl, amino, oralkylamino moiety. Thus, a protected form as used herein may comprise aprotected hydroxyl, protected carboxyl, or a protected amino oralkylamino moiety. Protection involves temporary blocking of the moietyso that a reaction can be carried out selectively at another reactivesite in a multifunctional compound. A protected amino or alkyl amino maybe protected by a protecting group, selected from protecting groupsincluding, but not limited to, carbamates (including methyl, ethyl andsubstituted ethyl carbamates (e.g., Troc), carbobenzyloxy (Cbz),tert-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc)),p-methoxybenzyloxycarbonyl (Moz or MeOZ), acetyl (Ac), benzoyl (Bz),benzyl (Bn), p-methoxybenzyl (PMB) 3,4-dimethoxybenzyl (DMPM),p-methoxyphenyl (PMP), succinyl (Suc), methoxysuccinyl (MeOSuc), formyl,urethane protecting groups, tosyl (Ts), other sulfonamides (e.g. Nosyl &Nps). For example, in certain embodiments, as detailed herein, certainexemplary oxygen protecting groups are utilized. A protected hydroxyl orcarboxyl may be protected by an oxygen protecting group, selected fromprotecting groups including, but not limited to, acetyl (Ac), benzoyl(Bz), benzyl (Bn), pivaloyl (Piv), methyl ethers, substituted methylethers (e.g., MOM (methoxymethyl ether), β-methoxyethoxymethyl ether(MEM), MTM (methylthiomethyl ether), BOM (benzyloxymethyl ether),p-methoxybenzyl (PMB), PMBM (p-methoxybenzyloxymethyl ether),substituted ethyl ethers, ethoxyethyl ethers, substituted benzyl ethers,methoxytrityl (MMT), tetrahydropyranyl (THP), trityl (Tr), silyl ethers(e.g., TMS (trimethylsilyl ether), TES (triethylsilylether), TIPS(triisopropylsilyl ether), TBDMS (t-butyldimethylsilyl ether), tribenzylsilyl ether, TBDPS (t-butyldiphenyl silyl ether, TOM(tri-iso-propylsilyloxymethyl)), esters (e.g., formate, acetate (Ac),benzoate (Bz), trifluoroacetate, dichloroacetate), carbonates, cyclicacetals and ketals. It will be appreciated that the present invention isnot intended to be limited to these protecting groups; rather, a varietyof additional equivalent protecting groups can be readily identifiedusing the above criteria and utilized in the present invention.Additionally, a variety of protecting groups are described in“Protective Groups in Organic Synthesis” Third Ed. Greene, T. W. andWuts, P. G., Eds., John Wiley & Sons, New York: 1999, the entirecontents of which are hereby incorporated by reference.

An “aprotic solvent” is used herein in accordance with standardterminology in the art to refer to a solvent which is incapable ofacting as a proton donor. Aprotic solvents include, but are not limitedto, dichloromethane, tetrahydrofuran, ethyl acetate, acetonitrile,dimethylformamide, dimethyl sulfoxide, acetone, hexane, pentane,benzene, toluene, 1,4-dioxane, diethyl ether, and chloroform.

A “protic solvent” is used herein in accordance with standardterminology in the art to refer to a solvent which is capable of actingas a proton donor. Generally, such a solvent has has a labile hydrogenatom bound to an oxygen or a nitrogen. Protic solvents include, but arenot limited to, water, alcohols (e.g. methanol, ethanol, isopropylalcohol), acetic acid, formic acid, hydrogen fluoride, and ammonia.

A “phosgene synthetic equivalent” used in a process of the inventionmay, for example, be carbonyldiimidazole, diphosgene, triphosgene, achloroformate e.g 4-nitrophenyl chloroformate or disuccinimidylcarbonate (DSC).

A chloroformate is a compound of formula ClC(O)OR. R may be, forexample, optionally substituted aliphatic, heteroaliphatic, aryl orheteroaryl.

Compounds of formula (I) and (II) as described herein may be of use asCCK₂/gastrin receptor antagonists and may be useful for the preventionand/or treatment of disorders associated with CCK₂/gastrin receptors,disorders caused by or associated with hypergastrinaemia and gastricacid-related disorders. Such disorders include disorders associated withCCK₂ receptor-bearing cells or failure or dysfunction of a physiologicalfunction in which gastrin is involved. Accordingly, examples ofdisorders that can be treated and/or prevented include, withoutlimitation, any one or more of gastric and duodenal ulcers, non-steroidanti-inflammatory drug (NSAID)-induced gastric ulceration, dyspepsia,gastro-oesophageal reflux disease (GORD), Barrett's oesophagus,Zollinger-Ellison syndrome (ZES), hypergastrinaemia induced by a protonpump inhibitor (PPI) or other acid-suppressant (including the effects ofwithdrawal) and conditions caused by hypergastrinaemia (such as boneloss, impaired bone quality and bone fractures), gastritis (including H.pylori-induced gastritis and complications of autoimmune chronicatrophic gastritis, such as gastric carcinoids and enterochromaffin-like(ECL)-cell hyperplasia), neuroendocrine tumours (not limited to gastriccarcinoids), parietal cell hyperplasia, fundic gland polyps, gastriccancer, colorectal cancer, medullary thyroid cancer, pancreatic cancer,and small cell lung cancer. The compounds may also be useful for theprevention and/or treatment of disorders induced by the dysfunction of aphysiological function controlled by the central or peripheral CCK2receptor, for example anxiety, nociception, pain, drug addiction,analgesic dependence and analgesia withdrawal reactions.

Compounds of formula (I) and (I-B), and embodiments thereof as describedherein, have at least one chiral carbon atom and may have more than onechiral carbon atom. The invention includes any enantiomeric form, at anylevel of optical purity, and mixtures thereof, both racemic andnon-racemic. Accordingly, all stereoisomeric forms of the compoundsdisclosed herein form part of the invention. An optically pure form ofan enantiomer as referred to herein has an enantiomeric excess (ee) ofat least 90%, preferably at least 95%, more preferably at least 98%, andeven more preferably at least 99%. ee may be assessed, for example, bychiral HPLC.

The compounds disclosed herein can exist in unsolvated as well assolvated forms for example with pharmaceutically acceptable solventssuch as water, ethanol, and the like, and it is intended that theinvention embrace both solvated and unsolvated forms. The compounds asdescribed herein, their enantiomers and mixtures thereof, may beprovided as the free compound or as a suitable salt or hydrate thereof.Salts should preferably be those that are pharmaceutically acceptable,and salts and hydrates can be prepared by conventional methods, such ascontacting a compound of the invention with an acid or base whosecounterpart ion does not interfere with the intended use of thecompound. Examples of pharmaceutically acceptable salts includehydrohalogenates, inorganic acid salts, organic carboxylic acid salts,organic sulphonic acid salts, amino acid salt, quaternary ammoniumsalts, alkaline metal salts, alkaline earth metal salts and the like.Basic compounds may form non-toxic acid addition salts with variousinorganic and organic acids, i.e., salts containing pharmacologicallyacceptable anions, including, but not limited to, malate, oxalate,chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acidphosphate, isonicotinate, acetate, lactate, salicylate, citrate,tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate,succinate, maleate, gentisinate, fumarate, gluconate, glucaronate,saccharate, formate, benzoate, glutamate, methanesulfonate,ethanesulfonate, benzenesulfonate, toluenesulfonate and pamoate salts.Acidic compounds may form salts with various pharmacologicallyacceptable cations, including alkali metal or alkaline earth metalsalts, particularly calcium, magnesium, sodium, lithium, zinc,potassium, and iron salts. Compounds that include a basic or acidicmoiety may also form pharmaceutically acceptable salts with variousamino acids.

EXAMPLES Abbreviations

-   DCM dichloromethane-   DIPEA N,N′-diisopropylethyl amine-   DMF N,N′-dimethylformamide-   DMS dimethyl sulphate-   GC gas chromatography-   HPLC high performance liquid chromatography-   Mel methyliodide-   MTBE methyltert-butylether-   THF tetrahydrofuran-   TLC thin layer chromatography-   UV ultra violet

Gas chromatography was carried out on a Shimadzu GC2014. HPLC wascarried out on an Agilent/HP 1100 reverse phase HPLC system. NMR spectrawere recorded on a 400 Mz Bruker Avance 111 spectrometer with QNP(1H/13C/19F/31P/Cryoprobe) or 500 Mz Bruker Avance 111 HD spectrometerwith dual (1H/13C). Elemental analysis (CHN) was performed on an ExeterAnalytical CE-440 elemental analyser. XPRD spectra were obtained on aPananalytical X′pert Pro diffractometer.

The following examples of the invention are provided to aidunderstanding of the invention but should not be taken to limit thescope of the invention. Unless otherwise described, reagents may becommercially available or prepared according to procedures in theliterature.

Reference Example—Process with Use of Azide Chemistry

The process of the invention avoids the need for potentially explosiveazide chemistry. Solely for reference purposes, a reaction scheme, inparts A and B, showing the use of azide chemistry as avoided by aprocess of the invention is provided below.

Part A

Part B

Racemic mixture (TR1) may, if desired, be resolved by chiral HPLCchromatography, for example with column: Chiralcel OD 250 mm×20 mm, 5μm; mode: super critical fluid (SFC); eluent: Methanol 40%, no modifier;flow: 50 mL/min and run time: 4 min.

Example 1: Synthesis of (TR2) and (TR2-A) via tert-Butyl(3-aminophenyl)methylaminocarbamate (N4)

(TR2) and (TR2-A) were synthesised according to the Scheme 1 below. Itwill be appreciated that this scheme can be applied generally to thesynthesis of compounds of formula (I) by variation of the startingmaterials N4 and 14-A, as appropriate.

Compound 14-A was synthesised according to Scheme 2 below:

Compound 11 was synthesised according to Scheme 3 below:

Compound N4 was synthesised according to Scheme 4 below:

Scheme 4 illustrates synthesis of N4 via N2 and N3. Whilst exemplaryreagents are illustrated in Scheme 4, it will be appreciated that thesemay be varied. For example, Boc in N2 to N4 may be replaced with analternative amino protecting group, such as Fmoc, Cbz or Ac. Conversionof 3-nitroaniline to N2 could, for example, use organic bases other thantriethlyamine, e.g. DIPEA. The methylation of N2 to N3, preferablyinvolves use of a base (e.g. KO^(t)Bu or NaH) and a methylating agent(e.g. DMS or Mel). The solvent in this step may be an aprotic solvent,preferably a polar aprotic solvent (e.g. DMF or THF). Reduction of N3 toN4 could be performed with iron metal or by hydrogenation on a catalystsuch as palladium on carbon or Raney Nickel.

4-Hydroxy-3,3-dimethyl-2-butanone (1)

Paraformaldehyde (465 g, 15.48 mol) and 3-methyl-2-butanone (1111 g,12.90 mol) were added to trifluoroacetic acid (6.0 L) and the mixtureslowly warmed to 90° C. in an oil bath over a one hour period. All theparaformaldehyde dissolved at about 50° C. The oil bath was cooled to75° C. (cardice addition to the oil). Once the flask content temperaturereduced to 85° C. a further charge of paraformaldehyde (465 g, 15.48mol) and 3-methyl-2-butanone (1111 g, 12.90 mol) was added. The mixtureslowly exothermed to about 92° C. (the oil bath was still at 75° C.).Once the flask content temperature had reduced to 85° C. the finalcharge of paraformaldehyde (465 g, 15.48 mol) and 3-methyl-2-butanone(1111 g, 12.90 mol) was added. After the exotherm was over, the mixturewas stirred at 90° C. for a further 8 hours before cooling back to roomtemperature overnight. GC (of a small sample added to water and adjustedto pH=14 with sodium hydroxide then extracted into DCM) indicated about2% 3-methyl-2-butanone and 86% product. The product solution was pouredinto a stirred mixture of ice (16 kg; extra cold from freezer) and solidsodium hydroxide (3 kg). A further charge of sodium hydroxide (about 260g) was added to just bring the pH to 14. GC indicated hydrolysis wascomplete. The aqueous solution was saturated with sodium chloride (about3 kg added) then without delay extracted with DCM (3×8 L). The combinedDCM layers were washed with saturated brine (3 L) and dried overanhydrous sodium sulfate. The solution was evaporated under vacuum togive a light brown liquid (about 3.7 kg). The crude product wasdistilled through a 20 cm Vigreux distillation column at about 95° C./45mmHg (A fore cut was removed and some residue remained afterdistillation) to give a near colourless product (2.85 kg, 63% yield, GCpurity=98%).

1-Bromo-4-hydroxy-3,3-dimethyl-2-butanone (2)

Compound 1 (2566 g, 22.09 mol) was dissolved in methanol (13 L) andstirred at 20° C. The reaction flask was covered to protect it fromlight. Bromine (200 g, 1.25 mol) was added over 15 minutes. After ashort induction period the reaction decolourised and a slight exothermoccurred. Once the mixture had decolourised it was cooled to 0° to 5° C.

Bromine (3300 g, 20.65 mol) was slowly added over a two hour periodwhile maintaining the temperature at 0°-5° C. (decolourisation was nowfast). GC indicated about 94% product and <1% starting material. Severalsmall after-peaks could also be seen by GC. Without delay the mixturewas poured into saturated brine solution (20 L) and ice (4 kg) thenextracted with DCM (4×8 L). The combined DCM extracts were washed withsaturated brine (2×5 L) and then dried over anhydrous sodium sulfate.The solution was evaporated under vacuum at 40° C. to give a lightyellow/brown liquid (4191 g, 97% yield, GC purity 91%).

1-Bromo-4-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-2-butanone (3)

Imidazole (645 g, 9.47 mol) was added to DCM (8.5 L) and cooled to −15°C. to −20° C. under a nitrogen atmosphere. Compound 2 (1650 g, 8.46 mol)was added to give a clear solution at −15° C. to −20° C.tert-Butyl-dimethylsilyl chloride (1365 g, 9.06 mol) was slowly addedwhile maintaining the temperature at −15° C. to −20° C. The mixture wasstirred for a further 3 hours at that temperature. GC indicated 78%product, less than 1% starter and 14% residual tert-butyl-dimethylsilylchloride. The reaction mixture was poured into cold water (7.5 L). Theaqueous layer was removed and re-extracted with more DCM (2 L). Thecombined DCM layers were washed with water (2×2 L) then with saturatedbrine (2×3 L) before drying over anhydrous sodium sulfate. The solutionwas evaporated under vacuum at 40° C. to give a yellow oil (2559 g, 97%yield, GC purity about 75%). ¹H NMR (400 MHz, CDCl₃) δ 4.24; (s, 2H);3.55; (s, 2H); 1.17; (s, 6H); 0.86; (s, 9H); 0.02; (s, 6H).

2-(2-Aminobenzoyl)pyridine (4)

2-bromopyridine (1075 g, 6.80 mol) in toluene (4.2 L) was cooled to<−65° C. while stirring under a nitrogen atmosphere. n-Butyl lithium(1.6 M in hexane; 4160 mL, 6.66 mol) was added over a one hour periodwhile maintaining the temperature <−60° C. The mixture was stirred at<−60° C. for 30 minutes before checking for the absence of2-bromopyridine by GC. A solution of 2-aminobenzonitrile (350 g, 2.96mol) in toluene (2.3 L) (may need warming slightly to dissolve) wasslowly added over a 30-minute period while maintaining the temperatureat <−60° C. The mixture was allowed to warm slowly to room temperaturewhile stirring overnight. The mixture was carefully poured into coldhydrochloric acid solution (1.96 L 32% hydrochloric acid, 3 L water and2 kg ice) while stirring. The mixture was stirred for a further hourbefore allowing the layers to separate. The lower aqueous layer wasremoved and the upper organic layer was extracted with hydrochloric acidsolution (350 mL of 32% hydrochloric acid and 3 L of water). Ice (4 kg)was added to the combined acidic aqueous layers before adjusting topH=10 with 35% ammonia solution (about 6.5 L). Add more ice as requiredto achieve a final temperature of 0-5° C. The slurry was stirred at 0-5°C. for a further 30 minutes. The slurry was filtered and washed withwater until free of ammonia. The product was dried in a circulated airoven at 50° C. (until a constant weight was achieved) to give ayellow/orange solid (558 g, 95% yield, 87% GC purity).

2-(Benzotriazol-1-yl)-2-(benzyloxycarbonylamino)-acetic Acid (8)

A vigorously stirred mixture of benzotriazole (512 g, 4.30 mol), benzylcarbamate (650 g, 4.30 mol) and glyoxylic acid monohydrate (396 g, 4.30mol) in toluene (12 L) was heated to reflux and water removed using aDean and Stark apparatus. Heating rate was adjusted to keep foamingdown. Water evolution ceased after about 150 mL had been collected. Asolid also formed in the stirred mixture. The mixture was heated atreflux for a further hour before slowly allowing to cool overnight. Thesolid was filtered off and pulled down hard for 30 minutes beforewashing with MTBE (2×1 L). The product was air dried at 40° C. (untilconstant weight was achieved) to give a near white solid (1330 g, 95%yield, single spot by TLC).

Benzyl-(benzotriazol-1-yl-[2-(pyridine-2-carbonyl)-phenylcarbamoyl]-methyl)-carbamate(9)

A mixture of crude compound 4 (2000 g, 10.09 mol) and compound 8 (3620g, 11.09 mol) in DCM (36 L) was cooled to 0-5° C. in a 60 L reactionvessel. 4-Dimethylaminopyridine (148 g, 1.21 mol) was added in one lot.1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2417 g,12.61 mol) was added in small portions over a 30-minute period whilemaintaining the temperature at 0-5° C. The mixture was stirred for afurther hour at 0-5° C. to give a clear dark brown solution. TLC (elute50% ethyl acetate in hexane) indicated that all compound 4 (Rf=0.7yellow spot) had been consumed and compound 9 (Rf=0.35) had formed.Saturated sodium bicarbonate solution (20 L) was added and the mixturestirred for 5 minutes. The aqueous layer was removed and the organiclayer dried over anhydrous sodium sulfate before evaporating undervacuum to give thick oil (about 7150 g, 140% crude yield).

Benzyl(2-oxo-5-pyridin-2-yl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-carbamate(10)

Crude compound 9 (about 7.15 kg) was dissolved in methanol (10 L) andstirred at room temperature. A solution of methanol saturated withammonia (10 L) was added in one portion. The mixture was stirred for onehour at room temperature. TLC (elute 50% ethyl acetate in hexane)indicated that compound 9 (Rf=0.35) had eliminated benzotriazol (Rf=0.5)to give an un-cyclised intermediate (Rf=0.1). The mixture was initiallywarmed to about 30° C. and then allowed to stir overnight while coolingto room temperature. A solid formed in the stirred mixture. TLC (elute50% ethyl acetate in hexane) indicated that the un-cyclised intermediate(Rf=0.1) had cyclised to form compound 10 (Rf=0.15). The slurry wasfiltered and the filter cake washed with cold methanol (1 L) followed byethyl acetate (3 L) and finally hexane (2 L). The filtrate was strippedto about half its original volume and allowed to stand for two days. Asecond crop was filtered off (if formed) and washed with cold methanol,ethyl acetate and hexane. The combined good crops were air dried at40-50° C. in a circulating air cabinet to give an off white solid (1785g). The material can be slurried in two volumes of DCM, filtered andre-dried to improve purity if required.

A total of 27.6 kg (92% HPLC purity) of crude compound 10 was made from114.4 kg of crude compound 9 using the above method. A DCM slurryreduced the yield to 25.9 kg (98% HPLC purity; 42% yield over two stepsfrom compound 4).

1H NMR (400 MHz, CDCl3) δ8.67; (1H,s), 8.61; (1H, d, J=4.1 Hz), 8.10;(1H, d, J=7.5 Hz), 7.84; (1H, dt J=1.4, 7.5 Hz), 7.50-7.28; (8H, m),7.20; (1H, t, J=7.5 Hz), 6.99; (1H, d, J=7.5 Hz), 6.65; (1H, d, J=8.2Hz), 5.37; (1H, d, J=8.2 Hz), 5.15; (2H, d, J=2.7 Hz)

Benzyl(1-[4-(tert-Butyl-dimethyl-silanyloxy)-3,3-dimethyl-2-oxo-butyl]-2-oxo-5-pyridin-2-yl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-carbamate(11)

Compound 10 (1040 g, 2.69 moles) was slurried in tetrahydrofuran (10.4L) under a nitrogen atmosphere at 0-5° C. Potassium tert-Butoxide (423g, 3.77 mol) was added in a single portion resulting in a 10° C.exotherm. A near clear solution formed briefly before another solidformed. The mixture was re-cooled to 0-5° C. Crude compound 3 (2080 g,6.72 mol crude with 5.04 mol active content) was slowly added over a30-minute period while maintaining the temperature at 0-5° C. Stirredfor a further 30 minutes. The mixture was warmed to 20-25° C. andstirred for a further hour. TLC (elute 50% ethyl acetate in hexane)indicated that compound 12 (Rf=0.55) had formed but some compound 10(Rf=0.15) remained. A silyl by-product spot (Rf=0.8) could also be seen.A further charge of potassium tert-butoxide (78 g, 0.70 mol) was addedin one lot and the mixture stirred for 20 minutes. TLC checkoccasionally indicated that all of compound 10 had been consumed. Ifsome compound 10 remains by TLC add extra crude compound 3 (200 g, 0.65mol) stir for 10 minutes. Charge extra potassium tert-butoxide (78 g,0.70 mol) and stir for 20 minutes. The reaction should now be completebut this step can be repeated until compound 10 is consumed. The mixturewas stirred for a further hour and then allowed to stand overnight atroom temperature. The reaction mixture was poured into 5% brine solution(20 L) and extracted with ethyl acetate (10 L and then 5 L). Thecombined organic extracts were washed with 5% brine solution (5 L) andthen dried over anhydrous sodium sulfate. The solution was evaporatedunder vacuum to give viscous oil (sometimes containing some crystals).The oil was slowly poured into hexane (15 L) allowing time a solid toform. The resulting slurry was stirred for 2 hours to form a fineslurry. The mixture was filtered and washed with hexane (2×3 L). Thefilter cake was air dried at 20-30° C. in a circulating air cabinet togive a tan solid (1291 g, 78% yield, 97.6% HPLC purity).

¹H NMR (400 MHz, CDCl3) δ8.63; (1H, d, J=4.8 Hz), 8.15; (1H, d, J=8.2Hz), 7.81; (1H, t, J=7.5 Hz), 7.47; (1H, t, J=7.5 Hz), 7.42-7.28; (6H,m), 7.23; (1H, t, J=7.5 Hz), 7.10; (1H, d, J=8.2 Hz), 6.73; (1H, d,J=8.2 Hz), 5.49; (1H, d, J=8.2 Hz), 5.20-5.10; (3H, m), 4.45; (1H, d,J=17.7 Hz), 3.67; (2H, s), 1.24; (3H, s), 1.19; (3H, s), 0.90; (9H, s),0.08; (3H, s), 0.05; (3H, s).

tert-Butyl (3-nitrophenyl)-carbamate (N2)

Triethylamine (915 g, 9.04 mol) and 4-(dimethylamino)-pyridine (30 g,0.25 mol) was added to a solution of 3-nitroaniline (833 g, 6.03 mol) intetrahydrofuran (6.1 L) at room temperature. The mixture was heated toreflux then external heating turned off. A solution ofdi-tert-butyldicarbonate (1448 g, 6.63 mol) in tetrahydrofuran (2.2 L)was added at such a rate to maintain reflux. The mixture was heated atreflux with external heating for a further 2 hours. TLC (elute 33% ethylacetate in hexane) indicated that all the 3-nitroaniline (Rf=0.6) hadbeen consumed and compound N2 (Rf=0.85) had formed. The mixture wasallowed to cool to room temperature overnight. Solvent was evaporatedunder vacuum and the residue dissolved in DCM (15 L). The mixture waswashed with water (2×8 L) then dried over anhydrous sodium sulfate. TheDCM solution was passed through a silica gel plug (1 kg) and washedthrough with more DCM (5 L) to remove residual4-(dimethylamino)-pyridine. The solution was evaporated under vacuum togive a thick slurry. Hexane (4 L) was added and the mixture allowed coolovernight. The mixture was filtered and washed with hexane (3 L). Thefilter cake was dried in a circulating air cabinet overnight to give atan solid (1205 g, 84% yield, single spot by TLC).

tert-Butyl methyl-(3-nitrophenyl)-carbamate (N3)

A solution of tert-butyl-(3-nitrophenyl)-carbamate (904 g, 3.79 mol) intetrahydrofuran (11.25 L) was cooled to 0-5° C. under a nitrogenatmosphere. Potassium tert-butoxide (555 g, 4.95 mol) was added in smallportions over a one hour period while maintaining the temperature at<10° C. The mixture was then stirred at about 10° C. for 90 minutesbefore re-cooling back to 0-5° C. Dimethyl sulfate (622 g, 4.93 moles)was slowly added over a one hour period while maintaining thetemperature at <10° C. The mixture was allowed to warm to roomtemperature while stirring overnight. TLC (elute 10% ethyl acetate inhexane) indicated that all N2 (Rf=0.35) had been consumed and N3(Rf=0.45) had formed. The mixture was carefully poured into diluteammonia solution (3 L of 33% w/w ammonia solution and 10 L of water) andstirred for one hour. The mixture was extracted into DCM (3×5 L). Thecombined organic extracts were washed with water (5 L) and then brine (5L) before drying over anhydrous sodium sulfate. The mixture wasevaporated under vacuum to give red/brown oil (943 g, 98% yield, 98.5%GC purity).

¹H NMR (400 MHz, CDCl₃) δ8.14; (1H, t, J=2.1 Hz), 7.98; (1H, dd, J=8.1,2.0 Hz), 7.61; (1H, d, J=8.1 Hz), 7.47; (1H, t, J=8.1 Hz), 3.31; (3H,s), 1.46; (9H, s).

tert-Butyl (3-aminophenyl)-methyl-carbamate (N4)

Triethylamine (30 mL) was added to a solution of tert-butylmethyl-(3-nitrophenyl)-carbamate (500 g, 1.98 mol) in methanol (2.5 L).Palladium on carbon (5% w/w; Johnson Matthey type 87L paste, 50% water;50 g) was carefully added under a nitrogen atmosphere and the mixturehydrogenated using a Parr shaker at 50 psi hydrogen pressure. Hydrogenuptake was rapid and the mixture exothermed from 20° C. to 75° C.Hydrogenation was continued for one hour after the exotherm had ended.TLC (elute 89% chloroform, 10% methanol and 1% ammonia solution)indicated that N3 (Rf=0.75) had been consumed and N4 (Rf=0.55) hadformed. The mixture was carefully filtered through a bed of celite ontop of a GF-F fibre pad. The filtrate was evaporated under vacuum todryness. The resulting solid residue was slurried in hexane (1000 mL)for one hour. The mixture was filtered and washed with hexane (500 mL).The product was dried in a vacuum oven at 40° C. to give a tan solid(429 g, 97% yield). 98.6% GC purity, melting range=100-102° C. (Thishydrogenation has also been carried out at atmospheric pressure).

¹H NMR (400 MHz, CDCl₃) δ7.09; (1H, t, J=7.9 Hz), 6.65-6.56; (2H, m),6.5; (1H, dd, J=8.1, 2.0 Hz), 3.65; (2H, br s), 3.22; (3H, s), 1.45;(9H, s).

3-Amino-1-(4-acetoxy-3,3-dimethyl-2-oxo-butyl)-5-pyridin-2-yl-1,3-dihydrobenzo[e][1,4]diazepin-2-one(13-A)

A 45% w/v solution of hydrogen bromide in acetic acid (2080 mL, 11.6mol) was diluted with more acetic acid (11 L) and stirred at roomtemperature. Compound 11 (2230 g, 3.63 mol) was added in one lot (with a4° C. exotherm). The mixture was warmed to 35-40° C. for 2 hours. TLC(of a small sample neutralised with saturated sodium bicarbonate andextracted into dichloromethane, elute 5% methanol in dichloromethane)indicated that all of compound 11 (Rf=0.95) had been consumed and thatonly a small trace of Cbz protected intermediate (Rf=0.45) remained. Themixture was evaporated under vacuum (75° C./<100 mbar) to remove most ofthe acetic acid. The thick residue was dissolved in cold water (20 L) at<10° C. and washed with dichloromethane (2×8 L) to remove benzyl bromideand silyl by-products. Each dichloromethane wash was back extracted withwater (3 L). Fresh dichloromethane (10 L) was added to the aqueoussolution. Solid sodium bicarbonate was added to the stirred mixtureuntil effervescence stopped and pH=8. The dichloromethane layer wasremoved and the aqueous layer extracted with more dichloromethane (5 L).The combined dichloromethane layers were dried over anhydrous sodiumsulfate and evaporated under vacuum to give a thick oil. Ethyl acetate(5 L) was added to the oil while still in the rotating Rotavap flask.The oil dissolved and a solid crystallised out. The slurry was cooled toroom temperature and filtered. The filter cake was washed well with coldethyl acetate. The mother liquor was evaporated to produce a furthercrop. The product was dried at 35° C. in a circulating air cabinet togive an off white powder (1250 g, 84% yield, 98.6% HPLC purity).

¹H NMR (400 MHz, CDCl₃) δ8.62; (1H, d, J=3.9 Hz), 8.17; (1H, d, 7.8 Hz),7.81; (1H, dt, J=2.0, 7.8 Hz), 7.49; (1H, dt, J=2.0, 7.8 Hz), 7.42-7.33;(2H, m), 7.23; (1H, dt, J=1.0, 7.8 Hz), 7.09; (1H, d, J=8.3 Hz), 5.10;(1H, d, J=18.0 Hz), 4.67; (1H, s), 4.43; (1H, d, J=18.0 Hz), 4.18; (2H,q, J=10 Hz), 3.65; (2H, br s), 2.47; (1H, br s), 2.08; (3H, s), 1.32;(3H, s), 1.28; (3H, s).

(R)-3-Amino-1-(4-acetoxy-3,3-dimethyl-2-oxo-butyl)-5-pyridin-2-yl-1,3-dihydrobenzo[e][1,4]diazepin-2-one(R)-mandelic acid salt (14-A R-mandelate Salt)

Small scale—Compound 13-A (28 g, 68.7 mmol) was slurried in acetonitrile(178 mL) at 20° C. R-mandelic acid (6.27 g, 41.1 mmol) was added and themixture stirred until a clear solution formed. Diethyl ether (59 mL) wasadded before slowly cooling the mixture down to −5° C. The mixture wasfiltered and washed with ice cold 30% diethyl ether in acetonitrile (40mL). The product was vacuum dried at 40° C. to give a near white solid(20.3 g, 43% ee R-isomer by chiral HPLC). The crude product wasdissolved in acetonitrile (89 mL) at about 45° C. and allowed to slowlycool to 20° C. while standing over a 2 hour period. Fibre like crystalsslowly formed. The mixture was filtered and washed with cold (−18° C.)acetonitrile (20 mL) followed by diethyl ether (40 mL). The productvacuum dried at 35° C. to give a white solid (8.2 g, 21% yield, 98.8% eeR-isomer by chiral HPLC).

Larger scale—Compound 13-A (1266 g, 3.10 mol) was slurried inacetonitrile (8050 mL) at 20° C. About half the solid seemed todissolve. R-Mandelic acid (283 g, 1.86 mol, 0.6 molar equiv.) was addedto the stirred mixture. The remaining solid slowly dissolved to form aclear yellow solution. Diethyl ether (2660 mL) was added. The solutionremained clear at 20° C. The mixture was slowly cooled to −5° C. over a30-minute period. As the temperature dropped below 5° C., the solutionmay be seeded with previously made R-mandelate salt. A very thicksuspension forms (almost solidified) that slowly thinned out whilestirring for a further 2 hours. The mixture was filtered (slow) andwashed with cold (−18° C.) 50% acetonitrile in diethyl ether (1.5 L) andthen with just diethyl ether (2.5 L). The product was dried at 35° C. ina circulating air cabinet overnight to give a near-white solid (1022gslightly damp). The solid can be slightly gummy if any acetonitrileremains during air drying. Chiral HPLC indicated that the salt wascomposed of about 69% R-isomer and 32% S-isomer. The crude product (1022g) was dissolved in acetonitrile (4.1 L) at about 45 ° C. Heated untiljust in solution and then allow to cool naturally immediately with onlyoccasional mixing. Prolonged heating or overheating seemed to results inproduct decomposition. Once the temperature had dropped below 35° C. thesolution may be seeded with previously made compound 14-A R-mandelatesalt (>99% ee by chiral HPLC). The mixture was slowly cooled to about20° C. over a 4-hour period with occasional stirring. The thick mixturewas filtered and washed with cold (about −10° C.) acetonitrile (1 L)followed by diethyl ether (2 L). The product was dried at 35° C. in acirculating air cabinet overnight to give a white crystalline solid (461g, 99.5% ee R-isomer by chiral HPLC, 26.5% yield).

Seeding with compound 14-A R-mandelate salt made by a procedurecorresponding to that above can be used to expedite crystallisation, butis not essential.

(R)-3-Amino-1-(4-acetoxy-3,3-dimethyl-2-oxo-butyl)-5-pyridin-2-yl-1,3-dihydrobenzo[e][1,4]diazepin-2-one(14-A)

Compound 14-A R-mandelate salt (4474 g, 7.98 mol) was dissolved in astirred mixture of saturated sodium bicarbonate (25 L) anddichloromethane (25 L) and stirred for 10 minutes. The aqueous layer wasremoved and back extracted with dichloromethane (5 L). The combineddichloromethane layers were washed with more saturated sodiumbicarbonate solution (10 L). The new aqueous layer was back extractedwith dichloromethane (5 L) again. The combined dichloromethane extractswere dried over anhydrous sodium sulfate. The free base solution wasevaporated down to a volume of 15 L. This solution was assumed tocontain 3260 g (7.98 mol) of compound 14-A. The solution was useddirectly in the next step. 99.6% HPLC purity, 99.3% ee R-isomer chiralHPLC purity.

¹H NMR (400 MHz, CDCl₃) δ8.62; (1H, d, J=4.1 Hz), 8.17; (1H, d, J=7.5Hz), 7.82; (1H, dt, J=1.3, 8.1 Hz), 7.50; (1H, dt, J=2.0, 7.8 Hz),7.42-7.33; (2H,m), 7.23; (1H, t, J=6.8 Hz), 7.09; (1H, d, J=8.2 Hz),5.10; (1H, d, J=18.0 Hz), 4.67; (1H, s), 4.43; (1H, d, J=18.0Hz), 4.18;(2H, q, J=10 Hz), 2.48; (1H, br s), 2.08; (3H, s), 1.56; (2H, br s),1.32; (3H, s), 1.28; (3H, s).

(R)-1[1-(4-Acetoxy-3,3-dimethyl-2-oxo-butyl)-2-oxo-5-pyridin-2-yl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]-3-(3-tert-butoxycarbonyl-methylamino-phenyl)-urea (18-A)

A slurry of 1,1′-carbonyldiimidazole (421 g, 2.60 mol) in DCM (3260 mL)was cooled to 0-5° C. while stirring under a nitrogen atmosphere. Asolution of compound N4 (577 g, 2,60 mol) in DCM (1630 mL) was slowlyadded over a 30-minute period while maintaining the temperature at 0-5°C. The 1,1′-carbonyldiimidazole slowly dissolved to form a light orangesolution during the addition. The solution was stirred at 0-5° C. for afurther hour before warming to 15-20° C. and stirring for a furtherhour. A 21.73% w/v solution of compound 14A (3751 mL, containing 815 g,2.00 mol) in DCM was slowly added over a 30-minute period whilemaintaining the temperature at 15-20° C. The mixture was stirred at thistemperature for a further 2 hours. TLC (Small sample quenched intosaturated sodium bicarbonate solution. Elute ethyl acetate) indicatedthat all of compound 14A (Rf=0.1) had been consumed and compound 18A(Rf=0.35) had formed. =The mixture was washed with saturated sodiumbicarbonate solution (2×6 L). Each wash was back extracted with DCM (2L). The combined DCM layers were dried over anhydrous sodium sulfate andevaporated under vacuum to give a thick oil (2020 g, still a littlesolvent-wet). Ethyl acetate (5 L) was added and evaporation continued toremove residual DCM from the mixture. The mixture was made-up to avolume of 7.25 L with ethyl acetate (a crude concentration of about 25%w/v). 85.8% HPLC purity with two earlier running components (6.9% and0.8%) and two later running components (3.9% and 0.6%).

Purification of Compound 18-A

A chromatography column was wet packed with 3 kg of silica gel in 79%ethyl acetate, 20% hexane and 1% triethylamine (the triethylamine isused only during column packing). About 1000 mL of compound 18A solution(containing about 250 g of crude product) was diluted to 2000 mL withethyl acetate and then hexane (500 mL) slowly added while stirring. Thisclear solution was charged onto the column. The column was eluted with20% hexane in ethyl acetate (about 35 L required) until the less polarimpurity was removed and then with ethyl acetate (about 35 L required)until compound 18A is removed. Good fractions were evaporated undervacuum to remove solvent. Evaporation was stopped while the product oilwas still mobile and before a thick tar/glass formed. HPLC purity 96.8%.

¹H NMR (400 MHz, CDCl₃) δ8.61; (1H, d, J=4.1 Hz), 8.15; (1H, d, J=7.5Hz), 7.79; (1H, dt, J=2.0, 7.5 Hz), 7.51; (1H, t, J=7.9 Hz), 7.42-7.30;(3H, m), 7.26; (1H, t, J=7.5 Hz), 7.19; (1H, t, J=8.1 Hz), 7.13-7.05;(2H, m), 6.93; (1H, d, J=7.5 Hz), 6.86; (1H, br s), 6.75; (1H, d, J=8.1Hz), 5.70; (1H, d, J=7.5 Hz), 5.03; (1H, d, J=18.4 Hz), 4.52; (1H, d,J=18.4 Hz), 4.16; (2H, q, J=11.0, 6.0 Hz), 3.21; (3H, s), 2.07; (3H, s),1.45; (9H, s), 1.29; (3H, s), 1.26; (3H, s).

(R)-1-[1-(4-Acetoxy-3,3-dimethyl-2-oxo-butyl)-2-oxo-5-pyridin-2-yl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]-3-(3-methylamino-phenyl)-urea (TR2-A)

Compound 18-A (1046 g) was dissolved in acetic acid saturated (about 1.5molar) with hydrogen chloride (11 L) to give a light orange solution.The mixture exothermed from 15 ° C. to 23 ° C. The mixture was stirredat room temperature for 3 hours. TLC (small sample neutralised withsodium bicarbonate and extracted into DCM; elute: ethyl acetate)indicated that all of 18-A (Rf=0.35) had been converted into TR2-A(Rf=0.20). Nitrogen was bubbled through the solution for one hour toreduce hydrogen chloride content. Most of the acetic acid was removedunder vacuum (65° C./<60 mmHg) to give a thick amber oil. The productwas dissolved in DCM (10 L) and poured into a stirred saturated solutionof sodium bicarbonate (15 L). More solid sodium bicarbonate was addeduntil effervescence stopped and pH=8. (Do not use a stronger base thanbicarbonate. Even carbonate will remove the acetate group). The DCMlayer was removed and the aqueous layer re-extracted with DCM (2×2L).The combined DCM extracts were dried over anhydrous sodium sulfate andfiltered through a bed of celite. The DCM solution was evaporated undervacuum to give a foamed-up oil. Ethyl acetate (5.5 L) was added to thematerial while still in the rotating rotary evaporator flask with thevacuum off. The oil dissolved and a solid slowly formed. The mixture wasallowed to cool to room temperature while standing overnight. Themixture was filtered and washed with ethyl acetate (4 L). The filtercake was pulled down hard and then dried in a vacuum oven at 35° C.overnight. The solid was broken-up and passed through a sieve beforedrying further in a vacuum at 35° C. for 2 days (no weight changebetween second and third day of drying) to give an off-white powder (740g). TR2-A may be recrystallized from ethyl acetate, if required. A totalof 3711 g (84% yield, 98.2% HPLC purity, 99.9% ee R-isomer chiral HPLCpurity) of compound TR2-A was made from about 5234 g of compound 18-Ausing the above method.

¹H NMR (500 MHz, CDCl₃) δ8.60; (1H, d, J=4.9 Hz), 8.15; (1H, d, J=7.9Hz), 7.77; (1H, dt, J=1.8, 7.9 Hz), 7.49; (1H, dt, J=1.8, 7.9 Hz), 7.38;(1H, dd, J=1.8, 7.9 Hz), 7.33; (1H, ddd, J=1.2, 4.9, 7.3 Hz), 7.25;(with CHCl₃ peak, t, J=7.3 Hz), 7.10; (1H, d, J=7.3 Hz), 7.03-6.93; (3H,m), 6.75; (1H, t, J=2.1 Hz), 6.52; (1H, dd, J=1.8, 7.3 Hz), 6.28; (1H,dd, J=1.8, 7.9 Hz), 5.72; (1H, d, J=7.9 Hz), 4.96; (1H, d, J=18.0 Hz),4.50; (1H, d, J=18.0 Hz), 4.14; (2H, q, J=10.6 Hz), 3.73; (1H, br s),2.77; (3H, s), 2.05; (3H, s), 1.26; (3H, s), 1.23; (3H, s).

(R)-1-[1-(4-Hydroxy-3,3-dimethyl-2-oxo-butyl)-2-oxo-5-pyridin-2-yl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]-3-(3-methylamino-phenyl)-urea (TR2)

Compound 18-A was dissolved in acetic acid saturated with hydrogenchloride at about 20° C. and stirred for about 3 hours. Most of theacetic acid was removed from the mixture under reduced pressure beforedissolving the residue in water. The mixture was neutralised with sodiumbicarbonate and then extracted into dichloromethane. The combinedextracts were dried over anhydrous sodium sulphate and then evaporatedunder reduced pressure to give a glass-like oil TR2-A, which was useddirectly in the next step.

TR2-A was dissolved in methanol. A solution of potassium carbonate inwater was added and the mixture stirred at about 20° C. for about 2hours. Most of the methanol was removed from the mixture under reducedpressure before dissolving the residue in water. The mixture wasextracted into dichloromethane. The combined extracts were dried overanhydrous sodium sulphate and then evaporated under reduced pressure togive a yellow glass-like oil. The yellow oil was purified by flashcolumn chromatography through silica gel, using gradient elution (1-3%methanol in dichloromethane). Good fractions were evaporated undervacuum to give TR2 as a pale yellow glass-like solid.

¹H NMR (400 MHz, CD₃Cl₃) δ8.60; (1H, d, J=4.0 Hz); 8.12; (1H, d, J=11.2Hz); 7.78; (1H, dt, J=8.0 and 2.4 Hz); 7.52; (1H, dt, J=7.2 and 2.0 Hz);7.39-7.32; (2H, m); 7.28-7.23; (1H, m); 7.20; (1H, d, J=10.0 Hz); 7.04;(1H, t, J=8.0 Hz); 6.94-6.85; (2H, m) 6.76; (1H, t, J=2.0 Hz); 6.55,6.30; (2H, 2×dd, J=8.0, 2.0 Hz and 8.4, 3.2 Hz); 5.70; (1H, d, J=7.8Hz); 4.91, 4.49; (2H, AB system, J_(AB)=22.0 Hz); (2H, AB system,J_(AB)=14.0 Hz); 3.16; (1H, br s); 2.78; (3H, s); 1.20, 1.19; (6H, 2×s).

Exact mass by positive ion electrospray mass spectroscopy M+H=515.2398m/z (theory: 515.2407 m/z for composition C₂₈H₃₁N₆O₄).

Example 2: Synthesis of (TR2-A) viatert-butyl(3-hydroxycarbamoylphenyl)methylcarbamate (N1)

Compound (TR2-A) was synthesized according to Scheme 5 below.

Compound N1 was synthesized according to Scheme 6 below.

Scheme 6 illustrates synthesis of N1 via 15 and 16. Whilst exemplaryreagents are illustrated in Scheme 6, it will be appreciated that thesemay be varied. For example, Boc in 15 to N1 may be replaced with analternative amino protecting group, such as Fmoc, Cbz or Ac. Conversionof methyl 3-aminobenzoate to 15 could, for example, use organic basesother than DIPEA, e.g. triethlyamine. The methylation of 15 to 16,preferably involves use of a base (e.g. KO^(t)Bu or NaH) and amethylating agent (e.g. DMS or Mel). The solvent in this step may be anaprotic solvent, preferably a polar aprotic solvent (e.g. DMF or THF).Conversion of 16 to N1 may be performed with a hydroxylamine salt (e.g.an HCl or sulphate salt) or hydroxylamine solution, a base (e.g. KOH)and a protic solvent (e.g. methanol).

Methyl 3-(tert-butoxycarbonylamino)benzoate (15)

To a 20.0 L, 3-necked round bottomed flask equipped with overheadstirrer, thermometer, nitrogen bubbler and reflux condenser was chargedacetonitrile (6.5 L), methyl-3-aminobenzoate (848 g, 5.6 mol),N,N-diisopropylethylamine (1.44 kg, 11.2 mol, 2.0 equivalents) anddi-tert-butyldicarbonate (2.0 kg, 9.16 mol, 1.63 equivalents). Anitrogen atmosphere was established and stirring was commenced. Thevessel contents were heated at 70° C. for 3 days after this time TLC(eluent: 1:1 hexane/ethyl acetate) revealed no starting materialremaining. Heating was then discontinued and the vessel contents cooledto ˜50° C. and transferred to a 20 L rotary evaporator. Solvent wasremoved under reduced pressure and the resulting beige/orange residuewas triturated with hexane (4.0 L) for 1 hour prior to filtration of theresulting solid. The recovered solid was re-slurried in hexane (4.0 L)overnight, filtered, washed on the funnel with hexane (2×0.5 L) andpulled dry. Damp weight yield=1213 g. The solid was dried in a vacuumoven at 40° C. (48 hours) to constant weight. Dried weight yield=1185 g,84.2%. This material was used directly in the next stage.

¹H NMR (400 MHz, CDCl₃) δ12.10; (1H, br s), 7.99; (1H, s), 7.91; (1H, d,J=7.5 Hz), 7.55-7.50; (1H, m), 7.43; (1H, t, J=7.5 Hz), 3.31; (3H, s),1.47; (9H, s) ppm.

Methyl 3-(tert-butoxycarbonylmethylamino)benzoate (16)

To a 20 L, flange flask equipped with overhead stirrer, thermometer and500 mL P-E dropping funnel was dissolved a solution of compound 15 (1075g, 4.28 mol) in DMF (13.4 L). Stirring was commenced and the vesselcontents were cooled to 0-10° C. in an ice/water/salt bath. Sodiumhydride (60% dispersion in oil) (256 g, 6.42 mol, 1.5 equivalents) wasadded portion wise over 20 minutes maintaining the internal temperatureat <10° C. Once complete, the reaction mixture was warmed to ambient,stirred for 1 hour and then re-cooled to 0-10° C. Dimethyl sulphate (863g, 6.84 mol, 1.6 equivalents) was added over 30 minutes and then thecooling bath was removed and flask contents warmed to ambient. Afterthis time TLC (eluent: 9:1 hexane/ethyl acetate+ninhydrin) revealed thedesired product (3) with no starting material remaining. The reactionmixture was then cautiously quenched into 6 M aqueous ammonia solution(18.0 L [12.0 L water+6.0 L of 0.880 ammonia]) and stirring of theresulting mixture was continued for 1 hour. After this time DCM (10.0 L)was added and stirring continued for an additional 30 minutes. Thebi-phasic layers were separated and the upper aqueous layer was backextracted with DCM (5.0 L). The combined organic layers were back washedwith water (5.0 L) and 5% w/w brine solution (5.0 L). The organic layerwas concentrated on the rotary evaporator to −2.5 kg and then washedwith water (2×10.0 L). The concentrate was then re-stripped under highvacuum (−50 mbar) to give a brown red oil. Total yield of compound16=1270 g, 112%. Residual mineral oil from the sodium hydride was foundto be present in the product (as seen by ¹H NMR) but as this posed norisk to ongoing processing then no further purification of this materialwas undertaken and it was used directly in the next stage. NMR conformedto the required structure.

¹H NMR (400 MHz, CDCl₃) δ7.90; (1H, s), 7.82; (1H, d, J=8.0 Hz),7.48-7.35; (2H, m), 3.90; (3H, s), 3.27; (3H, s), 1.44; (9H, s) ppm.

tert-Butyl-(3-hydroxycarbamoylphenyl)methylcarbamate (N1)

To a 20 L, flange flask equipped with overhead stirrer, thermometer andreflux condenser was charged methanol (3.7 L) and hydroxylaminehydrochloride (644 g, 9.27 mol, 2.0 equivalents). Stirring was commencedand the vessel contents heated to near reflux to dissolve the solid. Thereaction mixture was then cooled to ˜40° C. and a pre-prepared solutionof potassium hydroxide (779 g, 13.89 mol, 3.0 equivalents) dissolved inmethanol (2.5 L) was added in one portion. The vessel contents were thencooled to room temperature and compound 16 (1229 g, 4.63 mol, 1.0equivalents) was added in one portion and stirring continued for 2hours. After this time TLC (eluent: 9:1 DCM/methanol) revealed residualstarting material remaining and hence the reaction mixture was warmed to35-40° C. for an additional 2 hours. TLC revealed no starting materialremaining and after cooling to room temperature the reaction mixture wasneutralised by the addition of acetic acid (612 g, 10.19 mol, 2.2equivalents). The mixture was then poured into water (20.0 L) andextracted with ethyl acetate (3×8.0 L). The combined organic layers wereback washed with 25% w/w brine solution (2×5.0 L) and dried over sodiumsulphate, filtered and filtrate stripped on the rotary evaporator (50°C.) to a thick paste. Hexane (2.5 L) was added to the warm paste beforecooling to room temperature. The resulting slurry was filtered, washedon the funnel with hexane (2×0.5 L) and pulled dry. The colourless solidwas air dried in a vacuum oven [no heat] until constant weight. Totalyield=847 g, 69%. NMR conformed to the required structure.

¹H NMR (400 MHz, CDCl₃) δ8.98 (1H, br s), 7.66; (1H, s), 7.48; (1H, d,J=7.5 Hz), 7.42-7.30; (2H, m), 3.25; (3H, s), 1.47; (9H,s) ppm.

(R)-1-[1-(4-Acetoxy-3,3-dimethyl-2-oxo-butyl)-2-oxo-5-pyridin-2-yl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]-3-(3-tert-butoxycarbonyl-methylamino-phenyl)-urea (18-A)

Compound N1 (8.50 g, 31.92 mmol, 1.3 molar equiv.) was slurried inacetonitrile at room temperature. Carbonyldiimidazole (5.20 g, 32.07mmol, 1.3 molar equiv.) was added in one lot (no exotherm noted)resulting in a clear solution. The solution was stirred at roomtemperature for 30 minutes and then heated to 60° C. for one hour beforere-cooling to room temperature. TLC indicated that all N1 had beenconsumed. Compound 14-A (10.0 g, 24.48 mmol) was added and the mixturestirred at room temperature for 2 hours. TLC indicated all but a smalltrace of 14-A had been consumed and a new relatively clean product hadformed. Most of the acetonitrile was removed under vacuum at 35° C. togive a thick oil (no change seen by TLC). The residual oil was dissolvedin dichloromethane (200 mL) and washed with saturated sodium bicarbonatesolution (2×150 mL). Dried over anhydrous sodium sulphate and strippedto a pinkish foamed-up oil (27.3 g). HPLC indicated this to be 45.4%compound 18-A with a 31.3% major impurity.

Preparation of TR2-A from Crude Compound 18-A (Made via the LossenMethod)

Crude compound 18-A (25 g) was dissolved in acetic acid saturated withhydrogen chloride (250 mL) and stirred at room temperature overnight.TLC indicated that the reaction was complete by comparison withpreviously prepared reference samples. Most of the acetic acid wasremoved under vacuum at 50° C. to give a viscous oil. The oil wasdissolved in water (250 mL) and neutralised by addition of solid sodiumbicarbonate while stirring. The mixture was extracted withdichloromethane (2×250 mL) and the combined extracts dried overanhydrous sodium sulphate before evaporating solvent under vacuum togive a foam/glass (18.1 g). TLC indicated clean conversion. HPLCindicated the product to be 40.9% TR2-A and 32.3% impurity. Followingflash chromatography HPLC indicated 69.0% TR2-A and 20.9% impurity.

Example 3: Alternative Synthesis of 2-(2-aminobenzoyl)pyridine (4)

A solution of morpholine (855 g, 9.81 mol) in toluene (10 L) was stirredto 90° C. while adding isatoic anhydride (1600 g, 9.81 mol) in 25 gportions over a 2.5 hour period. Carbon dioxide was rapidly evolvedduring the addition. The resulting mixture (referred to below as themorpholide solution) was stirred at 90° C. for a further hour beforecooling to room temperature.

In a separate vessel a solution of 2-bromopyridine (3580 g, 22.66 mol)in toluene (12 L) was cooled to <−60° C. under a nitrogen atmosphere.n-Butyl lithium (1.6 M in hexane) (14.10 L, 22.56 mol) was slowly addedover a 2-hour period while maintaining the temperature at <−60° C. Themixture was stirred at <−60° C. for a further 30 minutes. The previouslyprepared morpholide solution was slowly added over a 4-hour period whilemaintaining the temperature at <−60° C. The mixture was allowed to warmslowly to room temperature while stirring overnight.

The reaction mixture was added to a stirred mixture of hydrochloric acid(32%) (6.5 L), ice (6 kg) and water (6 L). The aqueous layer was removedand filtered. More ice (8 kg) was added followed by the slow addition ofammonium hydroxide (33%) (about 3.0 L) until pH=9. The resulting solidwas filtered and washed with water. The filter cake was dried to give2-(2-aminobenzoyl)pyridine (compound 4) as a yellow/brown solid (1630 g)in 80% crude yield.

Example 4: Solubility Study

A solubility study confirmed that (TR1) and (TR2-A) are more soluble inaqueous solution than YF476; and (TR2-A) is more soluble in aqueoussolution than (TR1). The test compound (2.5 mg of solid; n=1) wasweighed in a clear glass vial and Britton-Robinson's buffer (0.5 mL) wasadded (pH 2.01, pH 3.06, pH 4.06, pH 5.08, pH 5.99, pH 6.98, and pH8.16). The solution was agitated at ambient temperature overnight usinga vial roller system, and then filtered (0.45 pm pore size; withoutpre-saturation). Two aliquots (50 μL) were sampled from the filtrate anddiluted with one volume of 0.1 N hydrochloric acid and methanol (1:1v/v) before analysis by HPLC-UV. A standard was prepared in DMSO at 10mg/mL (n=1) which was then diluted 10-fold in 0.1 N hydrochloric acidand methanol (1:1 v/v) to give a 1 mg/mL solution. The concentration oftest compound in the filtrate was quantified relative to theconcentration standard.

Analysis was done using a gradient HPLC-UV system with a total cycletime of 6 min. The UV detection between 220 nm and 300 nm was done usinga photodiode array detector. Total response was monitored.

Aqueous solubility Solubility advantage YF476 (TR1) (TR2-A) ((TR1)/((TR2-A)/ ((TR2-A)/ pH (μg/mL) (μg/mL) (μg/mL) YF476) YF476) TR1) 2.012650 5000 4190 1.9 1.6 0.8 3.06 99.7 645 730 6.5 7.3 1.1 4.06 5.9 58.2218 9.9 36.9 3.7 5.08 1.4 9.8 56 7 40.0 5.7 5.99 1.3 11.6 47.2 8.9 36.34.1 6.98 1.4 5.84 51 4.2 36.4 8.7 8.16 1.5 7.81 45.4 5.2 30.3 5.8

The solubility advantage of (TR1) and (TR2-A) over YF476 is especiallypronounced at pH 4-6, which is the pH range of the part of the smallintestine—duodenum to terminal jejunum or mid ilium—where most drugabsorption takes place. This enhanced solubility is an indicator that(TR1), (TR2), (TR3) and (TR2-A) are likely to be more bioavailable, andtherefore better drug candidates than YF476.

The values given in the table above are for crystalline YF476 and(TR2-A) and amorphous (TR1).

Crystalline (TR2-A) had almost the same solubility profile as amorphous(TR2-A), and is therefore likely to have comparable oralbioavailability. This is surprising because crystalline YF476 is poorlybioavailable and had to be converted to an amorphous form (spray-drieddispersion) to increase solubility and oral bioavailability. This shouldnot be necessary with (TR2-A).

Aqueous solubility (TR2-A) (TR2-A) amorphous crystalline pH (μg/mL)(μg/mL) 2.01 5000 4190 3.06 683 730 4.06 282 218 5.08 128 56 5.99 53.447.2 6.98 43 51 8.16 40.2 45.4

Example 5: Morphology Studies

In contrast to YF476, studies indicate that (TR1) and the pureenantiomers (TR2) and (TR3) prefer an amorphous state over a crystallinestate.

Initial attempts to crystallise (TR2) and (TR3) were unsuccessful,indicating preference for an amorphous state. Indeed, XRPD analysis of(TR2) confirmed an amorphous state. This is indicative of an advantageover YF476 in terms of the formulation of a suitable pharmaceuticalcomposition. YF476 is crystalline, which contributes to poor solubilityand bioavailability. Amorphous YF476 can be used to increasebioavailability, but requires stabilization, which can be achieved as asolid dispersion on hydroxypropyl methyl cellulose by spray-drying.Formulation of (TR) (in racemic, non-racemic or enantiomerically pureform), which prefers an amorphous state, would avoid the need for thisstabilization.

Example 6: CCK Receptor Antagonism

(TR2) and (TR3) were compared with YF476 and YM022 in CCK₁ and CCK₂receptor functional assays with the following assay criteria.

Receptor assay (antagonist Measured Detection effect) Source StimulusIncubation component method CCK₁ Human CCK-8s 10 min cAMP HTRF (human)recombinant (300 nM) 37° C. (CHO cells) CCK₂ Human CCK-8s 10 min cAMPHTRF (human) recombinant  (10 nM) 37° C. (CHO cells) HTRF: Homogeneoustime-resolved fluorescence cAMP: cyclic adenosine monophosphate CHO:Chinese hamster ovary

The results of the assays are shown in the table below:

Selectivity K_(B) CCK₁ CCK₂ (CCK₁)/ IC₅₀ K_(B) IC₅₀ K_(B) IC₅₀ (CCK₁)/K_(B) Antagonist (nM) (μM) (nM) (nM) IC₅₀ (CCK₂) (CCK₂) YF476 160 240.52 0.064 308 375 TR2 1000 150 2.5 0.31 400 484 TR3 8500 1300 99.0 12.086 108 YM022 — — 0.55 0.68 — —(TR2) and (TR3) were potent CCK₂ receptor antagonists and less potentCCK₁ receptor antagonists. In the CCK₂ assay, (TR2) compared favourablyto YF476 and YM022: (TR2) was only about 5-fold less potent than YF476and YM022; and although affinity of (TR2) for the CCK₂ receptor wasabout 5-fold lower than that of YF476, it was twice that of YM022.Furthermore, the selectivity of (TR2) for the CCK₂ receptor over theCCK₁ receptor was 30% higher than the selectivity of YF476. The potencyof the antagonists is expressed as IC₅₀, the concentration of antagonistthat causes a half-maximum inhibition of the control agonist response.The affinity of the antagonist for the receptor is expressed as K_(B),the concentration of antagonist, which would occupy 50% of the receptorsat equilibrium.

Example 7: Receptor Binding Screen

The potential of (TR2) and (TR3) to bind to other cellular and nuclearreceptors was tested in a panel of 80 receptors. The assay usedradiolabelled receptor ligands (agonist or antagonist, depending on thereceptor), and the ability of the test compounds to inhibit ligandbinding was measured by scintillation counting. No significant receptorbinding (other than CCK₂ and CCK₁) was found.

Example 8: Pre-Clinical Studies: Proliferation of Cells In Vitro

The potency of (TR2) and (TR3) was tested in a sulphorhodamine-B (SRB)proliferation assay in a human gastric adenocarcinoma cell line stablytransfected with the human gastrin/CCK₂ receptor gene (AGS_(GR)). SRB isa fluorescent dye that binds to proteins, so cells with a high rate ofprotein synthesis (proliferative cells) will show high levels offluorescence in the SRB assay. The gastrin fragment G17 has ananti-proliferative effect on AGS_(GR) cells. So, when treated with G17,the cells show lower levels of fluorescence in the SRB assay. (TR2) and(TR3) were compared with the positive controls YF476 and YM022. (TR2),YF476 and YM022, at a concentration of 100 nM, all completely inhibitedthe anti-proliferative effects of G17 (10 nM). (TR3), at a concentrationof 500 nM, had the same effect. None of the compounds tested affectedAGS_(GR) cell proliferation in the absence of G17.

Example 9: Pre-Clinical Studies: Rats with a Gastric Fistula

The effect of subcutaneous injections of YF476, (TR2) and (TR3) onpentagastrin-stimulated gastric acid secretion was tested in consciousrats with a chronic gastric fistula. All treatments dose-dependentlyinhibited the acid secretion response. ED₅₀ values for YF476, (TR2), and(TR3) were 0.012, 0.03 and 0.3 μmol/kg, respectively.

Example 10: Pharmacokinetics in Healthy Subjects

In an initial study, healthy volunteers took a single oral dose of 100mg (TR2) as an active pharmaceutical ingredient (API) in a capsule.Plasma concentrations were measured. The area under the curve of plasmaconcentrations of (TR2) after a single oral dose of 100 mg of activepharmaceutical ingredient (AUC=439.1) was about twice that observed fora similar formulation of a single oral dose of YF476 100 mg (AUC=198.5).Thus, (TR2) was observed to be more bioavailable than YF476.

In further clinical studies, healthy volunteers (n=8) took single oraldoses of 5, 15, 50 and 100 mg (TR2) as an active pharmaceuticalingredient (API) in a capsule. Plasma concentrations were measured. Themean area under the curve (AUC) of plasma concentrations of (TR2) aftera single oral dose of 100 mg of API (AUC_(0-24 h) (ng·h/mL)=241.5) wasabout three times that observed for a similar formulation of a singleoral dose of YF476 100 mg (AUC_(0-24 h)=81.3; n=10). Thus, (TR2) wasobserved to have better oral bioavailability than YF476 in the healthysubjects.

Healthy volunteers (n=8) took single oral doses of 5, 15, 25 and 50 mg(TR2-A) as API in a capsule (TR2-A (crystalline) in hard gelatincapsules with no excipient, no processing of the API). Plasmaconcentrations of (TR2) and (TR2-A) were measured. The area under thecurve of plasma concentrations of (TR2) after a single oral dose of 50mg of (TR2-A) API (AUC_(0-24 h)=212.5) was about the same as thatobserved for a similar formulation of a single oral dose of (TR2) 100 mg(AUC_(0-24 h)=241.5). Thus, (TR2-A) was observed to have better oralbioavailability than (TR2) in the healthy subjects. Moreover, the plasmaconcentrations of (TR2-A) were low (AUC_(0-24 h)<10), showing that(TR2-A) is acting as a prodrug for (TR2).

Example 11: Clinical Studies: Pharmacodynamic Effect in the HealthySubject

Pentagastrin induces gastric acid secretion, and thereby increases H⁺concentration. In an initial study, in a healthy volunteer, single oraldoses of 5, 25 and 100 mg of (TR2) administered in conjunction withpentagastrin infusion were observed to cause similar dose-dependentinhibition of the increase in H+concentration of gastric aspirateinduced by the intravenous infusion of pentagastrin as observed forcorresponding dosing of YF476 with pentagastrin infusion. Thus, thepotency of (TR2) as a CCK₂ receptor antagonist was similar to that ofYF476 in the healthy subject.

In further clinical studies, in healthy volunteers, single oral doses of5, 15, 50 and 100 mg of (TR2) or 5, 15, 25 and 50 mg (TR2-A) wereadministered in conjunction with pentagastrin infusion (i.v. dose 0.6μg/kg/h for 2 h). (TR2) and (TR2-A) were observed to cause similardose-dependent inhibition of the increase in H⁺ concentration of gastricaspirate induced by the intravenous infusion of pentagastrin as observedfor dosing of

YF476 with pentagastrin infusion. 100 mg of (TR2) and 50 mg (TR2-A)caused similar inhibition of the increase in H⁺ concentration of gastricaspirate induced by the intravenous infusion of pentagastrin as observedfor dosing of 100 mg YF476. Thus, the potency of (TR2) as a CCK₂receptor antagonist was similar to that of YF476 in healthy subjects,and the potency of (TR2-A) is greater than that of both (TR2) and YF476.The observed results showed that (TR2) supresses the effect ofpentagastrin in a dose-dependent manner, and that a lower dose of(TR2-A) than (TR2) was required for full suppression.

Embodiments of the invention have been described by way of example andthese embodiments are to be considered as illustrative rather thanrestrictive. It will be appreciated that variations in form and detailcan be made without departing from the true scope of the invention,which is to be defined by the appended claims.

1. A process for producing a compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein R₁ is: (i)—CH₂C(O)C(R₂)(R₃)—L—R₄ or —CH₂CHOHC(R₂)(R₃)—L—R₄, in which: R₂ and R₃are each, independently, H or C₁₋₃ aliphatic, halo, or C₁₋₃haloaliphatic, or wherein R₂ and R₃ together with the intervening carbonatom to which they are bonded, form a C₃₋₆ carbocyclic moiety; L is abond or C₁₋₃ alkylene; and R₄ is —OR₅ or —SR₅, wherein R₅ is hydrogen,optionally substituted alkyl (e.g. C₁₋₆ alkyl, such as methyl), aprotecting group or —C(O)R₆, wherein R₆ is optionally substitutedaliphatic, heteroaliphatic, aromatic or heteroaromatic moiety; (ii)—CH₂CHOH(CH₂)_(a)R₇ or —CH₂C(O)(CH₂)_(a)R₈ in which a is 0 or 1 and R₇and R₈ are selected from alkyl and cycloalkyl groups and saturatedheterocyclic groups optionally substituted at a hetero-atom; or (iii) anoptionally substituted aliphatic moiety; W and X are, independently,hydrogen, halo, C₁₋₈ alkyl or C₁₋₈ alkoxy; and rings A and B are each,independently, a monocyclic aryl or heteroaryl, optionally substitutedwith one or more substituents independently selected from halo, hydroxy,amino, nitro, carboxyl, carboxamido, cyano, —SO₃H, and optionallysubstituted C₁₋₈ alkyl, C₁₋₈ alkoxy, C₁₋₈ alkylamino or di(C₁₋₈alkyl)amino, wherein any one or more substituent on R₁, ring A or ring Bmay be unprotected or in a protected form; wherein the processcomprises: providing a reaction mixture by adding a compound of formula(I-A), a compound of formula (I-B) and a phosgene synthetic equivalentor phosgene to an aprotic solvent, to form a compound of formula (I)

wherein the phosgene synthetic equivalent is carbonyldiimidazole (CDI),diphosgene, triphosgene, a chloroformate or disuccinimidyl carbonate.2-3. (canceled)
 4. The process of claim 1, wherein the phosgenesynthetic equivalent or phosgene is carbonyldiimidazole.
 5. The processof claim 1, wherein the process comprises the additional step ofdeprotection to remove one or more protecting groups, wherein any one ormore substituents on R₁, ring A or ring B is in a protected form.
 6. Theprocess of claim 1, wherein the process comprises step (a) of providinga reaction mixture by adding a compound of formula (I-A), a compound offormula (I-B) and a phosgene synthetic equivalent or phosgene to anaprotic solvent, to form a compound of formula (I), wherein the compoundof formula (I-A) and the phosgene synthetic equivalent or phosgene areadded to the solvent prior to addition of the compound of formula (I-B).7. The process of claim 1, wherein the aprotic solvent is ethyl acetate,dichloromethane, acetonitrile or toluene.
 8. The process of claim 1,wherein R₁ is —CH₂C(O)C(R₂)(R₃)—L—R₄.
 9. The process of claim 1,wherein: (a) at least one of ring A and ring B is unsubstituted orsubstituted phenyl or pyridyl; and/or (b) W and X are, independently H,halo, C₁₋₃ alkyl or C₁₋₃ alkoxy.
 10. The process of claim 1, wherein:(a) at least one of ring A and ring B is unsubstituted, monosubstitutedor disubstituted phenyl or unsubstituted, monosubstituted ordisubstituted 2-, 3- or 4-pyridyl: and (b) W and X are both H.
 11. Theprocess of claim 1, wherein ring A is phenyl having a meta substituentchosen from NHMe, NMeEt, NEt₂, F, Cl, Br, OH, OCH₃, NH₂, NMe₂, NO₂, Me,(CH₂)_(n)—CO₂H, CN, CH₂NMe₂, NHCHO and (CH₂)_(n)—SO₃H where n is 0-2;unsubstituted phenyl or 2-, 3- or 4-pyridyl optionally substituted witha substituent selected from F, Cl, CH₃ and CO₂H; and Ring B is 2-, 3- or4-pyridyl or phenyl.
 12. The process of claim 1, wherein the compound offormula (I) is a compound of formula (II):

or a pharmaceutically acceptable salt thereof, wherein R₂, R₃, L and R₄are as defined in claim 1, the compound of formula (I-A) is a compoundof formula (II-A), and the compound of formula (I-B) is a compound offormula (II-B)

wherein PG is a protecting group.
 13. The process of claim 1, wherein R₂and R₃ together with the intervening carbon atom to which they arebonded, form a C₃₋₄ carbocyclic moiety, or wherein R₂ and R₃ are each,independently, H or C₁₋₂ alkyl; and L is a bond or C₁₋₃ alkylene. 14.The process of claim 1, wherein R₂ and R₃ are each, independently, C₁₋₂alkyl and L is —CH₂—.
 15. The process of claim 1, wherein R₁ is—CH₂C(O)C(R₂)(R₃)—L—R₄, R₄ is —OR₅ or —SR₅, R₅ is hydrogen, methyl or—C(O)R₆, and R₆ is optionally substituted aliphatic, heteroaliphatic,aromatic or heteroaromatic moiety.
 16. The process of claim 1, R₆ issubstituted or unsubstituted C₁₋₆ aliphatic.
 17. The process of claim 1,wherein R₆ is methyl.
 18. The process of claim 1, wherein R₄ is —OR₅ andR₅ is —C(O)R₆.
 19. The process of claim 1, wherein the compound offormula (I) or (II) is a compound selected from:

or a pharmaceutically acceptable salt thereof.
 20. The process of claim19, wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.
 21. The process of claim1, wherein the compound of formula (I) or (II) is a compound of formula(III):

or a pharmaceutically acceptable salt thereof, wherein R₁₁ is selectedfrom

wherein R6 is as defined in any of claims 1 and 15 to
 17. 22. Theprocess of claim 21, wherein the compound is a compound of formula (IV):

or a pharmaceutically acceptable salt thereof.
 23. The process of claim1, wherein the compound of formula (/) or (II) is a compound (TR) or(TR-A):

or a pharmaceutically acceptable salt thereof.
 24. The process of claim23, wherein the compound is a compound (TR2) or (TR2-A):

or a pharmaceutically acceptable salt thereof.
 25. The process of claim1, wherein the compound of formula (I) is YF476:

or a pharmaceutically acceptable salt thereof.
 26. A process accordingto claim 24 for producing a compound of formula (TR2-A):

wherein the process comprises: (a) providing a reaction mixture byadding a compound of formula (II-A), a compound of formula (II-Ba) and aphosgene synthetic equivalent or phosgene to an aprotic solvent, to forma compound of formula (TR2-A-PG)

wherein PG is a protecting group, optionally a Boc protecting group; and(b) deprotecting the compound of formula (TR2-A-PG) to form a compoundof formula (TR2-A). 27-29. (canceled)
 30. The process of claim 1,wherein, when R₁ is —CH₂CHOH(CH₂)_(a)R₇, —CH₂C(O)(CH₂)_(a)R₈, or anoptionally substituted aliphatic moiety, the reaction is maintained at atemperature of no more than 30° C. and the reaction is carried out inthe absence of a base.